The foremost challenge to the effective treatment of cocaine addiction is the lack of FDA approved pharmacotherapy for this illicit drug. This DP1 proposal directly addresses this concern by performing clinical Phase I/II medication development and evaluation studies to determine the efficacy and safety of l-tetrahydropalmatine (l-THP) as an anti-addiction medication for cocaine dependence. l-THP, a major active single compound isolated from the Chinese herbal medicine Yanhusuo, has been used in clinical practice as an analgesic (commercial name: Rotundine) in China for more than 40 years. It has been reported that l-THP acts on dopamine (DA) receptors as a DP1 partial agonist/D2 antagonist and also interacts with D3 receptor. In addition, it has low affinity binding to alpha1 and 5HT1A receptors. l-THP attenuates cocaine self-administration and brain-stimulation reward in rats and relieves craving in heroin addicts. The mechanism for this action of l-THP is unknown. It could be related to its DA receptor activity, as the dopaminergic system plays a critical role in the activation of brain reward pathways. More importantly, it could be that l-THP binds to multiple monoamine receptors that provide efficacy as a natural cocktail-like cocaine antagonist. Since, it is well known that cocaine non-selectively inhibits several monoamine transporters. Nevertheless, the unique pharmacological profile makes l-THP an excellent candidate for anti-addiction medication. The extensive animal and preclinical pharmacology and toxicity data resulting from decades of studies on l-THP in China provide a solid safety foundation for our proposed translational study. We plan to obtain IND approval of l-THP from the FDA, after which we will conduct clinical phase I and phase II trials. If this transition from animal studies to human clinical studies is successful, it will provide proof of concept that l-THP is an effective medication for cocaine addiction.